Scopine and sgopoline esters of alpha



United States Patent i 2,927,925 SCOPINE AND SCOPOLINE ESTERS F ALPHA, ALPHA-DIPHENYL PROPIONIC ACID Harold E. Zaugg, Lake Forest, lll., assignor to Abbott lllliaillaloratories, North Chicago, 111., a corporation of No Drawing. Application October 13, 1958 Serial No. 766,671

7 Claims. j (Cl. 260-292 The present invention is directed to the scopine and scopoline esters of. u,a-diphenyl propionic acidrepresented by the formula: I

C-C-R C O ited solubility in common organic solvents. The basic esters and more particularly their hydrogen chloride addition salts possess interesting pharmacological properties and are useful as anti-spasmodics, gastric-antisecretory agents, anti-Parkinson agents and tranquilizers. For such use, they can be administered orally or by injection and in suppository form if desired.

The new compounds may be prepared by the reaction of 'a,a-diphenyl propionyl chloride with scopine or scopoline. The reaction is carried out in the presence of a hydrogen chloride acceptor such as pyridine or triethylamine. Good results are obtained when employing-substantially equimolecular proportions of the reactants. V The reaction takes place smoothly at a temperature of from 20 C. to 125 C. with the formation of the desired ester product and amine hydrochloride of reaction. In a preferred method of operation, the reaction is carried out in the presence of an inert organic solventsuch as benzene, carbon tetrachloride or acetone.

In carrying out the reaction, the a,u-diphenyl propionyl chloride dissolved in an inert organic solvent, preferably benzene, is added slowly with stirring to a mixture of scopine or scopoline and a hydrogen chloride acceptor such as pyridine. The reaction mixture is then allowed to stand at room temperature if a scopine ester is desired or heated at the boiling temperature and under reflux if a scopoline ester is desired for a period of time to complete the reaction. The amine hydrochloride of reaction is removed by filtration or dissolved in water. The resulting filtrate or aqueous solution is'then made alkaline to liberate the basic ester product which is thereafter ex-- EXAMPLE I Scopine ester of a,a-diphenyl propionic'acid Q l a a -it CHr-CHCH 2,927,925 Patented Mar. 8, 1960 boiling temperature and under reflux for a periodoi two v hours. Following the heating period, the benzene and excess thionyl chloride were removed by distillation un- 1' der reduced pressure to obtain an a,u-diphenyl propionyl chloride product as a viscous liquid residue. Five grams (.032 mole) of scopine and 30'milliliters of pyridine were thereafter added to the acid chloride product and the resulting mixture allowed to stand at room temperature for two days. Fifty milliliters ofwater were then added and the reaction rnixture'made strongly alkaline with a saturated aqueous solution of sodium carbonate to liberate the desired ester which was extracted with ether. The ether extract was dried over anhydrous sodium sulfate and a slight stoichiometric excess of ethereal hydrogen chloride added thereto to precipitate the hydrochloride salt of the scopine ester of a,a-diphenyl propionic acid as a crystalline solid, which after recrystallization from isopropyl alcohol melted at 158l60 C.

Analysis-Calm. for C H NO -HCl: C=69.07%; H=6.55%; N=3.'50%. Found: C=69.64%; H=7.82%;

EXAMPLE II,

Scopoline ester of a,a-diphenyl propionic acid 9.78 grams (.04 mole) of a,a-diphenyl propionyl chlo-" ride prepared as described in Example I was dissolved in milliliters of dry benzene and added dropwise with stirring over a period of ten minutes to a mixture of 6.1 grams (.06 mole) of triethylamine and 6.2 grams (.04 mole) of scopoline in 75 milliliters of dry benzene. The resulting mixture was heated at the boilingtemperature and under reflux for 18 hours to complete the reaction. Upon completion of the reaction, the reaction mixture was extracted with an aqueous solution of hydrochloric acid containing equal parts by weight of acid and water.

The acid extract was made strongly alkaline with asaturated aqueous solution of sodium carbonate to liberate the desired scopoline ester product which was thereafter extracted with chloroform. After removal of the chloroform by distillation, the resulting residue was dissolved in absolute ethyl alcohol and a slight stoichiometric excess of ethereal hydrogen chloride added thereto. The solid scopoline hydrochloride which precipitated was removed by filtration and upon the addition of dry ether to the filtrate, there was obtained a hydrochloride salt of the scopoline ester of -a,a-diphenyl propionic acid as a crystalline solid. This salt product was recrystallized from isopropyl alcohol and after drying for 20 hours in What Iclaim-as my' invention is: and

1. The scopine-ester of a,-a-dipheny1 propionic acid.

2. The scopoline ester of-a,u-dipheny1 propionic acid. a

'3. A non-toxic acid addition salt of the scopine ester of a chdiphenyl propionic acid. 5 I; I

'4. A non-toxic acid additionsalt of the scopoline ester I [-0133 E of a,c-diphenyl propionic'acid. GH-.OH:

5. The hydrochloride of the scopine ester of agx-di- I V phenyl propionic acid.

- diphenyl propionic acid.

6. The hydrochloride of the scopoline ester of oc,oc- 10 andinon-toxlc"acldfaddltlon Salts thereof Referen es C't d n the fil t 7. A compound selected from the class consisting of c l e 1 e of ms patent esters corresponding to the formulas I ED STATES PATENTS 2,748,133 Karrer et a1. May 29, 1956 Z V E 15 2,800,476 -smu etgal July 23, 1957 CO H I|\'CHa l/ 2,872,452 ,ZeileetaL. ....V. Feb. 3, 1959 O JH:--OH- H 

7. A COMPOUND SELECTED FROM THE CLASS CONSISTING OF ESTERS CORRESPONDING TO THE FORMULAS 